Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. A high cholesterol level is a well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing between the prodomain and catalytic domain. This processing is required for PCSK9 to be secreted and to undertake its biological activity. Our goal is to identify compounds that prevent the processing of PCSK9, thus prevent its secretion and its ability to participate in the degradation of the LDL receptor. To that end, we will integrate virtual (computer) screening methods and cell-based assays to identify lead compounds that can potentially be optimized to produce a cholesterol lowering drugs. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen million of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. The specific aims of this work are to: 1) Use virtual screening methods to identify compounds that stabilize the PCSK9 zymogen and prevent its processing. 2) Determine the ability of the selected compounds to stabilize the PCSK9 zymogen and prevent its processing in an in vitro assay. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a segment of the population having very high cholesterol. Our goal is to develop new cholesterol lowering drugs that could have an effect on all individuals with high cholesterol levels, including that segment of the population having very high cholesterol. [unreadable] [unreadable] [unreadable]